Regulation of class switch recombination and somatic mutation by AID phosphorylation.
Regulation of class switch recombination and somatic mutation by AID phosphorylation.
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DOI：
10.1084/jem.20081319
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发表时间：
2008-10-27
期刊：
影响因子：
--
通讯作者：
Nussenzweig MC
中科院分区：
文献类型：
--
作者：
McBride KM;Gazumyan A;Woo EM;Schwickert TA;Chait BT;Nussenzweig MC
激活诱导的胞苷脱氨酶（AID）是一种增变酶，通过将尿嘧啶：鸟嘌呤错配引入DNA中来启动B淋巴细胞中的体细胞突变和类别转换重组。修复途径处理这些错配以在IG可变区中产生点突变或在开关区DNA中产生双链DNA断裂。然而，艾滋病也可以产生脱靶DNA损伤，包括癌基因突变。因此，在抗体应答成熟期间，需要严格调节AID以维持基因组稳定性。已经提出AID在丝氨酸38（S38）处的磷酸化调节其活性，但这尚未在体内测试。使用质谱和免疫化学方法的组合，我们发现，除了S38，AID也在位置苏氨酸140（T140）磷酸化。S38或T140突变为丙氨酸不影响催化活性，但干扰体内类别转换和体细胞超突变。这种效应在AID水平有限的单倍不足小鼠中特别明显。虽然S38对这两个过程同样重要，但T140磷酸化优先影响体细胞突变，这表明翻译后修饰可能有助于在超突变和类转换之间做出选择。
Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching.
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影响因子：
64.8
作者：
Liu, Man;Duke, Jamie L.;Schatz, David G.
通讯作者：
Schatz, David G.
DOI：
10.1084/jem.20040373
发表时间：
2004-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
McBride KM;Barreto V;Ramiro AR;Stavropoulos P;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
64.8
作者：
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作者：
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通讯作者：
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影响因子：
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作者：
Barreto, VM;Ramiro, AR;Nussenzweig, MC
通讯作者：
Nussenzweig, MC